CA2264960C - External formulation containing loxoprofen - Google Patents
External formulation containing loxoprofen Download PDFInfo
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- CA2264960C CA2264960C CA002264960A CA2264960A CA2264960C CA 2264960 C CA2264960 C CA 2264960C CA 002264960 A CA002264960 A CA 002264960A CA 2264960 A CA2264960 A CA 2264960A CA 2264960 C CA2264960 C CA 2264960C
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
- C12P7/42—Hydroxy-carboxylic acids
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Abstract
Problem: to provide a favorable antiphlogistic/analgesic containing loxoprof en or a medically acceptable salt thereof. Means for resolution: an antiphlogistic/analgesic for external use containing loxoprofen or a medical ly acceptable salt thereof and crotamiton.
Description
CA 02264960 1999-02-26DESCRIPTIONEXTERNAL FORMULATION CONTAINING LOXOPROFENTECHNICAL FIELDThe present invention relates to an anti-inflammatoryanalgesic external formulation containing Loxoprofen or itspharmaceutically acceptable salt as an active ingredient.BACKGROUND ARTA sodium salt of Loxoprofen (formal name: 2-[pâ(2âoxocyclopentylmethyl)phenyl] propionic acid), otherwise known asLoxoprofen sodium, has excellent efficacy as a phenylpropionic acidtype nonsteroidal anti-inflammatory agent and is widely used asa medicine for internal use under the trade name of "Loxonin."By the way, Loxoprofen sodium is a prodrug. When orallyadministered, it is metabolized in the body into a transâOH form(formal name: 2â[p-(transâ2âhydroxycyclopentylmethyl)phenyl]propionic acid), which exhibits excellent anti-inflammatoryactivities, as is known in the art [Matsuda et al. Japanese Journalof Inflammation, Vol. 2, No. 3, Summer, pp. 263 to 266 (l983)].An enzyme (a ketoneâreducing enzyme) which is associated.with thisCA 02264960 2000-04-20metabolism, mainly exists in the liver and kidney [Tanaka et al.,Japanese Journal of Inflammation, Vol. 3, No. 2, Spring, pp, 151to 155 (l983)], and the trans-OH fornxis known.to exhibit inhibitoryactivityagainstcyclooxygenase,apuostaglandinproducingenzyme,approximately 80 times as potently as Loxoprofen sodium [Matsudaet al. Japanese Journal of Inflammation, Vol. 2, No. 3, Summer,pp.263 to 266 (1983)]. Accordingly, it has been understood thatLoxoprofen sodium must pass through the liver or kidney, where itis activated, before Loxoprofen sodium can exhibit its excellentanti-inflammatory analgesic activities.Thus, when Loxoprofen sodium is used as an externalformulation, it should not be treated in the same manner asantiâinflammatory analgesics, such as indomethacin, ibuprofen andketoprofen, in case of which the drug itself provides apharmacological effect.However, hitherto, many patent applications have been filedfor external formulations containing an anti-inflammatoryanalgesic as an active ingredient, in particular, for bases forexternal formulations, and some of them cite an anti-inflammatoryanalgesic as an example of an active ingredient that is containedin the formulation or that can be added to the base, and further,some of them cite Loxoprofen sodium as a specific example of theCA 02264960 1999-02-26anti-inflammatoryanalgesic. Mostoftheseapplications,however,simply cite Loxoprofen as a mere example of the antiâinflammatoryanalgesic in the specification. Although some of these patentapplications refer to crotamiton as an example of a solvent foractive ingredients, which is one of the constituent features ofthe present application, none of the applications, in fact, doesspecifically disclose a formulation containing Loxoprofen andcrotamiton.On the other hand, in respect to Loxoprofen and its sodiumsalt, the external formulation are disclosed concretely in (1)Japanese Patent Application Laid Open No. Hei 4â997l9, (2) JapanesePatent Application Laid Open No. Hei 8-165251, and (3) JapanesePatent Application Laid Open No. Sho 57-4919.(1) is an invention on a novel base containing a certaintype of fatty acid ester and polyhydric alcohols and intends toincrease the speed at which an active ingredient permeates throughthe skin and a transdermal patch the base of which containsLoxoprofen sodium is prepared as an example there.(2) discloses a specific solvent, [2â(2âmethoxy-l-methylethyl)-5-methylcyclohexanol] and, an external formulationcontaining said solvent, a.patch containing Loxoprofen.is preparedas an example there, and its tackiness and safety to the skin areCA 02264960 1999-02-26evaluated in the test examples. However, none of the patentapplications refertxnpharmacological effectscofloxoprofen.sodiumin the case where it is administered in the form of an externalformulation.In addition, when the present inventors prepared an externalformulation of Loxoprofen sodium containing a fatty acid ester anda polyhydric alcohol in accordance with (1) and observed it withthe passage of time, crystals of Loxoprofen were deposited. Ingeneral, when an external formulation of a certain compound isprepared, a solvent is added in order to avoid the crystallizationand deposition of the active ingredient. The selection of anoptimal solvent is an important element for the design of aformulation. Depending on the type of a selected solvent, theremay occur a decreased release of the active ingredient from thebase and a decreased transfer of it to the affected part becauseof the insufficient dissolution of the drug, thereby failing toprovide sufficient therapeutical effects. In other words, asolvent that is optimal for a particular active ingredient cannotbe expected to be also optimal for other active ingredients.On the other hand, Japanese Patent.Application Laid Open No.Sho 57-4919 (the above mentioned (3)) describes, in test examples,the pharmacological effects as external formulations of'a solutionCA 02264960 2000-04-20of Loxoprofen in croton oil and of an ointment obtained by simplyadding Loxoprofen sodium to Plastibase 50W. croton oil, however,is a toxic substance which is used as an irritant and cocarcinogenin the research of cancer [THE MERCK INDEX, twelfth edition, pp.2665] so that it is inappropriate to mix such a substance into amedicine. In addition, the efficacy of a formulation comprisinga combination of Loxoprofen sodium and Plastibase 50W does notexhibit dosage dependence.DISCLOSURE OF THE INVENTIONProblems to Be Solved by the InventionAs described above, Loxoprofen is a prodrug, it is itstrans-OH form, an active metabolite, that exhibits stronganti-inflammatory analgesic activities, and.the enzyme that servesto convert Loxoprofen into an active metabolite mostly exists inthe liver and kidney. Hence, the present inventors supposed thatfor topical administration, the transcutaneous absorption oftrans-OH form of Loxoprofen allows the trans-OH form to bemaintained at its applied site in a larger amount to achieve anexcellent anti-inflammatory analgesic activities than thetranscutaneous absorption of Loxoprofen. However, tests by thepresent inventors on the transâOH form for its transcutaneousCA 02264960 1999-02-26absorption revealed that the trans-OH form could Very hardly beabsorbed.As a result of the intensive research on anti-inflammatoryanalgesic external formulation containing Loxoprofen sodium as anactive ingredient, the present inventors have found that (i)Loxoprofen as such has a superior permeability through the skinto the trans-OH form, which is an active metabolite, so thattranscutaneous administration enables a sufficient amount ofLoxoprofen to be accumulated in the skin, and that (ii) if asufficient amount of Loxoprofen.is retained in the skin over a longperiod of time, it is surprisingly transformed by the ketone-reducing enzyme into the trans-OH form even in the skin and aneffective amount of trans-OH forn1can.be maintained therein. Withrespect to the above problem of the formulation of Loxoprofen, thepresent inventors have found that the use of crotamiton as a solventprevents Loxoprofen from being deposited in the form of crystal,thereby providing an external formulation of Loxoprofen that hashigh stability and that shows no skin irritation. That is, mixingcrotamiton as a solvent into an external formulation of Loxoprofenprevents Loxoprofen from being deposited as crystals, and as aresult a formulation is obtained which has excellent uniformityin the distribution of the active ingredient. This formulationCA 02264960 1999-02-26enables a substantial increase in the rate and amount oftranscutaneous absorption of Loxoprofen and also a continuoussupply of Loxoprofen, thereby allowing a sufficient concentrationof Loxoprofen to be persistently maintained in the skin at theapplied site. Then, as confirmed first by the present inventors,Loxoprofen is converted into the trans-OH form in the skin so asto allow a sufficient amount of trans-OH form to be maintained atthe applied site. As a result, it has been found that applicationofthisformulationprovidesanexcellenttopicalanti-inflammatoryanalgesic effect and.that the formulation.shows no skin irritation.Based on these findings, the present inventors have completed thepresent invention.(Means for Solving the Problems)The present invention relates to:(1) a nmthod for producing a trans-OH form comprisingconvertinglnxoprofencnritspharmaceuticallyacceptablesaltintoa trans-OH form thereof with a ketoneâreducing enzyme existing inthe skin; and(2) an anti-inflammatory analgesic external formulationcontaining Loxoprofen or its pharmaceutically acceptable salt andcrotamiton.The anti-inflammatory analgesic external formulationCA 02264960 2000-04-20described in (2) is preferably an external formulationcharacterized in that:(3)applicatnxioftheexternalformulationcausesLoxoprofenor its pharmaceutically acceptable salt to be metabolized into atrans-OH form thereof in the skin and wherein the trans-OH formis higher in concentration i.n a dermal layer of the skin at an appliedsite than in blood plasma.Of the antiâinflammatory analgesic external formulationdescribed in (2) or (3), more preferred is:(4) an external formulation wherein the content of crotamitonis 0.5 to 5% by weight of the total weight of the formulation;(5) an external formulation wherein the content of crotamitonis 1 to 2% by weight of the total weight of the formulation;(6) an external formulation wherein the content of Loxoprofenor its pharmaceutically acceptable salt is 0.1 to 5% by weight ofthe total weight of the formulation;(7) an external formulation wherein the content of Loxoprofenor its pharmaceutically acceptable salt is 0.15 to 2% by weightof the total weight of the formulation; or(8) an external formulation wherein the content of Loxoprofenor its pharmaceutically acceptable salt is 0.5 to 2% by weight ofthe total weight of the formulation.CA 02264960 2000-04-20Another preferred antiâinflammatory analgesic externalformulation is an arbitrary combination of elements each selectedfrom the groups consisting of (2) and (3), (4) and (5), and (6)to (8).In addition to Loxoprofen or its pharmaceuticallyâacceptablesalt and crotamiton, the anti-inflammatory analgesic externalformulationlnentioned above can include an additives commonlyrusedin external formulations. Preferred examples of such anti-inflammatory analgesic external formulations include in additionto Loxoprofen or its pharmaceutically acceptable salt andcrotamiton:(9) an external formulation containing 0.5 to 80% by weightof a solvent and/or a skin permeation accelerator of the total weightof the formulation;(10) an external formulation containing 3 to 30% by weightof the formulation of a water-soluble polymer of the total weight;(11) an external formulation containing 5 to 20% by weightof a water-soluble polymer of the total weight of the formulation;(12) an external formulation containing 5 to 95% by weightof an oil-soluble polymer of the total weight of the formulation;CA 02264960 2000-04-20(13) an external formulation containing 10 to 80% by weightof an oil-soluble polymer of the total weight of the formulation;(14) an external formulation containing 5 to 60% by weightof a moisturizer of the total weight of the formulation; or(15) an external formulation containing 10 to 45% by weightof a moisturizer of the total weight of the formulation.Further, formulations which include two or more elementsselected from (10) to (15) are also preferred. [However, (10) and(11) cannot be selected simultaneously and (14) and (15) cannotbe selected simultaneously.]Furthermore, it is another object of this invention to providean anti-inflammatory analgesic external formulation described inany one selected from (2) to (15) above, in the form of a patch,an ointment, a cream, a lotion, or an aerosol.According to this invention, the term "pharmaceuticallyacceptable salt" in the definition of "Loxoprofen or itspharmaceutically acceptable salt" refers to a salt of a cation witha carboxyl group that is contained in the molecule of Loxoprofen.Such salts preferably include alkali metal salts such as sodium10CA 02264960 2000-04-20salt, potassium salt, and lithium salt; alkaline earth metal saltssuch as calcium salt and magnesium salt; metal salts such as aluminumsalt, iron salt, zinc salt, copper salt, nickel salt, and cobaltsalt; ammonium salts; amine salts such as tâoctylamine salt,dibenzylamine salt, morpholine salt, glucosamine salt, salt of analkyl ester of phenylglycine, ethylenediamine salt, N~methylglucamine salt, guanidine salt, diethylamine salt,triethylamine salt, dicyclohexylamine salt, N,Nââdibenzylethylenediamine salt, chloroprocaine salt, procaine salt,diethanolaminesalt,Nâbenzylphenethylaminesalt,piperazinesalt,tetramethylammonium salt, tris(hydroxymethyl) aminomethane salt,and other such organic salts; and amino acid salts such as glycinesalt, lysine salt, arginine salt, ornithine salt, glutamic acidsalt,andasparticacidsalt. Thepharmaceuticallyacceptablesaltis more preferably a water-soluble salt and most preferably a sodiumsalt.Moreover, when left in the air or recrystallized, thePLoxoprofen.or its pharmaceuticallyracceptable salt" absorbs wateror the solvent used for recrystallization to become a hydrate orsolvate, which is also included in this invention.Whether a certain external formulation is a formulationwherein "applicatitniof the external formulation causes LoxoprofenllCA 02264960 1999-02-26or its pharmaceutically acceptable salt to be metabolized into atransâOH form thereof in the skin and wherein the concentrarionof transâOH form is higher in a dermal layer of the skin at an appliedsite than in blood plasma" can be checked by applying the externalformulation to, for example, test animals such as rats or mice andmeasuring the concentrations of trans-OH form.(ug/ml) in the bloodplasma and in the dermal layer of the skin at the applied site ata certain time (for example, four or eight hours) after theapplication. Specifically, this can be easily checked byconducting experiments according to the method described in "TestExample 3" described later.With respect to this invention, the content of Loxoprofensodium in the external formulation is not limited to any particularrange as long as formulation is feasible, but is preferablyrbetweenO. 1% by weight (more preferably 0. 15% by weight and most preferably0.5% by weight) and 5% by weight (more preferably 2% by weight)ofthetotalweightcï¬ftheformulation. Anexcessivelysmallamountof active ingredient provides insufficient efficacy, while anexcessively large amount of active ingredient provides noadvantages and is thus not cost-effective.The content of crotamiton used as a solvent is notparticularly limited as long as formulation is feasible, but is12CA 02264960 1999-02-26preferably between 0.5% by weight (more preferably 1% by weight)and 5% by weight (more preferably 2% by weight) of the total weightof the formulation.The pH of the external formulation is preferably between 4.0(more preferably 5.0 and most preferably 5.5) and 7.5 (morepreferably 7.0 and most preferably 6.5). 'The present external formulation may include various basesuseiforcommonexternalformulations,forexample,anothersolventthat can be used with crotamiton; a skin permeation accelerator,a water-soluble polymer that can be used as an adhesive agent and/ora filmâformer; an oil-soluble polymeric compound that can be usedas an adhesive agent and/or a tackifier; a moisturizer; asurfactant; a propellant; and other pharmaceutically acceptableadditives, without limitation, unless they do not have adverseeffects.Other solvents that dissolve Loxoprofen or itspharmaceutically acceptable salt is not particularly limited aslong as it can be used with crotamiton without providing adverseeffects, and is selected from, for example, water, alcohols,pharmaceutically acceptable fatty acids and their esters, and oilycomponents such as animal oils, vegetable oils, and terpenecompounds.13CA 02264960 2000-04-20If water is used, its content is preferably between 20% byweight (more preferably 40% by weight) and 80% by weight (morepreferably 60% by weight) of the total weight of the formulation.The alcohols may be any common alcohol without particularlimitation as long as it has no adverse effect. Such an alcoholincludes,forexample,aliphaticalcoholssuchasnmthanol,ethanol,propyl alcohol, and isopropyl alcohol; aliphatic polyhydricalcohols such as propylene glycol, octanediol, 1,3-butanediol,ethylene glycol, polyethylene glycol, glycerol, and D-sorbitol;and aromatic aliphatic alcohols such as benzyl alcohol. Thecontent of such an alcohol is preferably between 0.5% by weight(more preferably 3% by weight) and 10% by weight (more preferably5% bywueight) of the total weight of the formulation. However, thecontent of propylene glycol, polyethylene glycol, glycerol, orD-sorbitol used as the moisturizer described later is not limitedto these values.The pharmaceutically acceptable fatty acid.and its ester maybe any common fatty acid and ester without particular limitationas long as they have no adverse effect. The pharmaceuticallyacceptable fatty acid and ester thereof is preferably a fatty acidthat has 3 (more preferably 10) to 30 (more preferably 20) carbonatoms, for example, capric acid, lauric acid, myristic acid,14CA 02264960 1999-02-26palmitic acid, oleic acid, linolic acid, stearic acid, lauryllactate, isopropyl myristate, isopropyl palmitate, oleyl oleate,diisopropyladipate,diisopropylsebacate,glycerolmonocaprylate,or ethylene glycol monoisooctanoate. Its ester is preferably analkyl ester having 5 (more preferably 12) to 50 (more preferably40) carbon atoms or an alkylene glycol ester haying 8 (morepreferably 12) to 30 (more preferably 24) carbon atoms. One or morefattyacidsandtheirestersmaybeusedincnmbination. Apmeferredfatty acid is oleic acid or lauryl lactate. The content of suchan fatty acid or its ester is preferably between 0.5% by weight(more preferably 1% by weight) and 20% by weight (more preferably15% by weight) of the total weight of the formulation.The oily component such as animal oil, vegetable oil, and aterpenecompoumdmaybeanycommonoilycomponentwithoutparticularlimitation as long as it has no adverse effect . Such oily componentsinclude, for example, almond oil, olive oil, tsubaki oil, persicoil, peppermint oil, soybean oil, sesame oil, minkcail, cotton seedoil, corn.oil, safflower oil, palnloil, eucalyptus oil, castor oil,hydrogenated castor oil, soybean lecithin, squalene, dlâ or 1-menthol, 1-menthone, limonene, pinene, piperitone, terpinene,terpinolene, terpinol, carbeol, d1-camphor, Nâmethylâ2-pyrrolidone, or liquid paraffin. This component is preferably15CA 02264960 1999-02-26peppermint or eucalyptus oil. One or more types of such oilycomponents may be used in combination. Its content is preferablybetween 0.5% by weight (more preferably 1% by weight) and 10% byweight (more preferably 5% by weight) of the total weight of theformulation.Excessive amounts of these solvents may cause separation ofthe oily component from the formulation obtained by kneading themwith a water-soluble base and the resulting formulation may causeskin irritation. Therefore, it is preferred that the solvents aremixed together in amounts not to cause the phenomena mentionedabove.The skin permeation accelerator may be any common one withoutparticularlimitathniasfarasjizdoesnotexertanyotherinfluence.Preferred skin permeation accelerators include, for example,alcohols and polyhydric alcohols such as ethanol, propylene glycol,1, 3âbutanediol, and 1,2,6-hexanetriol; fatty acids such as lacticacid,oleicacid,linolicacid,andmyristicacid,andtheiresters;and animal oil, vegetable oil, and a terpene compound such aspeppermintoil,lâmenthol,d1-camphor,andN=methyl-2âpyrrolidone.These skin permeation accelerators can be also used as solventsor as the moisturizers described later.The water-soluble polymer that can be used as an adhesive16CA 02264960 1999-02-26agent and/or film-former may be any common compound withoutparticularlimitathmiasfarasiizdoesnotexertanyotherinfluence.Suchwater-solublepolymersinclude,forexample,polyacrylicacid;sodium polyacrylate; an acrylic ester copolymers and theiremulsions; cellulose derivatives such as methylcellulose,Dethylcellulose, carboxymethylcellulose, and sodiumcarboxymethylcellulose; gum arabic; gelatin; casein; polyvinylalcohol; polyvinylpyrrolidone; methyl vinyl ether/maleic acidanhydride copolymer and its emulsion; and natural polysaccharidesuch as agar. One or more types of these compounds may be used incombination and their content is preferably between 3 % by weight(more preferably 5% by weight) and 30% by weight (more preferably20% by weight) of the total weight of the formulation.If a water-soluble polymer such as polyacrylic acid or sodiumpolyacrylate is used, activated alumina, synthetic aluminumsilicate, or aluminum hydroxide can be used as an aluminum compoundthat can exhibit a cross-linking reaction.In addition, acryl starch; polyhydric alcohol such asglycerol, propylene glycol, polyethylene glycol, or D-sorbitol ispreferably used as a moisturizer, and one or more such compoundsmay be used in combination. Their content is preferably between5% by weight (more preferably 10% by weight) and 60% by weight (more17CA 02264960 1999-02-26preferably 45% by weight) of the total weight of the formulation.The oil-soluble polymer that can be used as an adhesive agentand/or a tackifier may be any common one without particularSuchlimitation as far as it does not exert any other influence.oil-soluble polymers include natural rubber, isoprene rubber,polyisobutylene rubber, styrene-butadiene rubber, a styrene-isopreneâstyrene block copolymer, a styrene-butadiene-styreneblock copolymer, a (meth) acrylic ester copolymer, silicone resin,rosin, polybutene, lanoline, Vaseline, plastibase, beeswax, andsolid paraffin. One or more such compounds may be used incombination, and their content is preferably between 5% by weight(more preferably 10% by weight) and 95% by weight (more preferably80% by weight) of the total weight of the formulation.Moreover, the desired amount of surfactant such as sorbitanmonooleate or polyoxyethylene sorbitan.monooleate; a pH regulatorsuch as tartaric acid or citric acid; or other pharmaceuticallyacceptable additives such as bentonite, kaolin, talc, or titaniumwhite can be used. Its content is preferably between 0.1% by weight(more preferably 0.5% by weight) and 15% by weight (more preferably10% by weight) of the total weight of the formulation.An external formulation according to this invention is18CA 02264960 1999-02-26preferably:(1) an antiâinflammatory analgesic external formulationcontaining, at least 0.1 to 5% by weight of Loxoprofen sodium, 0.5to 5% by weight of crotamiton, 0.5 to 80% by weight of a solventand/or a skin permeation accelerator, 3 to 30% by weight ofwater-soluble polymer and/or 5 to 95% by weight of oil-solublepolymer, and 5 to 60% by weight of moisturizer, all of the totalweight of the formulation.It is more preferably:(2) an antiâinflammatory analgesic external formulationcontaining, at least 0.15 to 2% by weight of Loxoprofen sodium,1 to 2% by weight of crotamiton, 0.5 to 80% by weight of a solventand/or a skin permeation accelerator, 5 to 20% by weight of awaterâsoluble polymer and/or 10 to 80% by weight of an oil-solublepolymer, and 10 to 45% by weight of a moisturizer, all based onthe total weight of the formulation.It is more preferably:(3) an antiâinflammatory analgesic external formulationcontaining, at least 0.5 to 2% by weight of Loxoprofen sodium, 1to 2% by weight of crotamiton, 0.5 to 80% by weight of a solventand/or a skin permeation accelerator, 5 to 20% by weight of awaterâso1uble polymer and/or 10 to 80% by weight of an oil-soluble19CA 02264960 2000-04-20polymer, and 10 to 45% by weight of a moisturizer, all of the totalweight of the formulation.The present anti-inflammatory analgesic externalformulation can generally be manufactured using the followingpreparation method.When an external formulation containing Loxoprofen as anactive ingredient is prepared, the present external formulationcan be obtained by dissolving Loxoprofen in crotamiton andoptionally adding thereto any of the above "various bases used forcommon external formulations".On the other hand, when an external formulation containinga pharmaceutically acceptable salt of Loxoprofen as an activeingredient is prepared, an external formulation can be obtainedby dissolving a pharmaceutically acceptable salt of Loxoprofen inan appropriate solvent (for example, water, methanol, ethanol orthe like), mixing this solution with crotamiton, and optionallyadding thereto any of the above "various bases used for commonexternal formulations". Any of the above "various bases used forcommon external formulations" can be added to the solution of theactive ingredient mentioned above or crotamiton before mixing thesolution with crotamiton.20CA 02264960 1999-02-26In. particular, when an external formulation containingLoxoprofensodhnnasanactiveingredientisprepared,thisexternalformulation can be specifically manufactured as follows.The mixture containing Loxoprofen sodium is prepared bydissolving 0.1 to 5% by weight of Loxoprofen sodium in 20 to 60%by weight of a solvent (for example, water), adding the solutionto a mixture of 5 to 20% by weight of sodium polyacrylate, 20 to35% by weight of glycerol, 1 to 5% by weight of alcohols, and anappropriateamountofa1pHregulatorsolutionthathasbeenpreparedin advance, and stirring the mixture. On the other hand, arnixturecontaining crotamiton is prepared by mixing 0.5 to 5% by weightof crotamiton, 0.5 to 10% by weight of a solvent and/or a skinpermeation accelerator, and an appropriate amount ofpharmaceutically acceptable additive. Then, the desired externalformulatuniispreparadbyaddingthenuxturecontainingcrotamitontothenuxturecontainingLoxoprofensodimnwhilststirring,addingthereto an appropriate amount of an aqueous suspension of a cross-linking reagent (for example, aluminunthydroxide gel or the like),and sufficiently kneading the mixture.A formulation with a smaller amount of water content can bemanufactured by adding 10 to 30% by weight of an oilâsoluble21CA 02264960 1999-02-26polymeric compound to the above external formulation.When an external formulation mainly containing oilâsolublepolymers is prepared, an oily formulation can be manufactured byusing isoprene or polyisobutylene as an adhesive agent, in the caseof solvent method, or a styrene-isobutylene block copolymer as anadhesiveagent,inthecaseofhot-meltnethod,andusingatackifieras well as crotamiton and the above oily component as a solventand skin permeation accelerator.According to this invention, the external formulationcontaining Loxoprofen sodium prepared in this manner is spread overan appropriate support, for example, a nonwoven fabric or flannel,andaapeel-off filntmade of polyethylene, polypropylene, polyesteror the like is applied to the exposed surface of the formulationthat is opposite to the surface thereof facing the support. Theresulting formulation can be used as a patch.Inaddition,withoutspreadingtheformulationonthesupport,the present external formulation can be used as an ointment or creamthat is applied to the affected part as it is.It can also be used as a lotion by diluting it with an aqueoussolvent (for example, water, ethanol or the like), and optionallyadding thereto a suspending agent (for example, gum arabic, sodiumalginate, sodium carmellose,or hydroxypropylcellulose) or an22CA 02264960 2000-04-20emulsifing agent (for example, sorbitan monooleate orpolyoxyethylene sorbitan monooleate) to homogenize the entiresolution.Alternatively, it can be used as an aerosol by diluting itwith a solvent to reduce viscosity, adding thereto a suspendingagent or an emulsifing agent, and filling the solution in anappropriate container together with a propellant (for example,dimethyl ether or liquefied natural gas).The dosage of the anti-inflammatory analgesic externalformulation of this invention may depend on the symptom, age ofthe patient, and the amount of active ingredients in the formulation,but it is desirable that an external formulation corresponding to0.005 g (preferably 0.01 g and more preferably 0.05 g) to 100 g(preferably 50 g and more preferably 10 g) per day of Loxoprofenis applied to the affected part of the adult . Due to its persistency,the present external formulation is expected to provide a sufficientanti-inflammatory analgesic effect when applied once a day, butthe daily dosage of an external formulation may be applied to theaffected part dividedly in several times.Theanti-inflammatoryanalgesicexternalformulatnmiofthis23, . .__....._.._.............. .....â..,...-........... .... i ...._i_......__......... ...l.CA 02264960 2000-04-20invention is effective on the prevention or treatment ofosteoarthritis, rheumatoid arthritis, lumbago, scapulohumeralperiarthritis,tendovaginitis,inflammationoftendonperipheries,humeralepicondylitis(tenniselbow),musclepain,orswelling/painafter trauma.BEST MODE FOR CARRYING OUT THE INVENTIONThis invention is described below with reference to examples,comparative examples, and test examples. However, the inventionis not limited to these examples.[Example]J Externalformulationcontaining2%<xfLoxoprofensodium2.268 g of Loxoprofen sodium dihydrate (equivalent to 2 g ofLoxoprofen sodium) was added to 8 ml of water and dissolved therein.Then, 0.6 g of tartaric acid was dissolved in 45.5 ml of water;11.5 g of sodium polyacrylate and 27 g of glycerol were added tothe solution and mixed together, and the aqueous solution ofLoxoprofen sodium prepared above was added to the mixture, wasfollowed by sufficient kneading to prepare a mixture containingLoxoprofen sodium (mixture A). Next, 2g of crotamiton, lg ofpeppermint oil, and 2.5 g of kaolin were mixed to prepare a mixturecontaining crotamiton (mixture B). MixtureI3was addedtx>mixture24CA 02264960 1999-02-26A.whilst stirring, and 1 ml of aqueous dispersion containing 0.05g of aluminum hydroxide gel was added to the mixture and theresulting mixture was mixed together. The weight of the mixtureobtainedwasneasured,then,waterwasaddeduntiltheweightbecame100 g, and the mixture was sufficiently kneaded. The resultingexternal formulation containing 2% of Loxoprofen sodiunlwas spreadover a nonwoven fabric so as to occupy in an amount of 10 g/10x14cm, and a polyethylene film was put on the formulation and theresulting formulation was cut into pieces of a certain desired sizefor use as a test sample.[Example 2] External formulation containing 1.2% of Loxoprofensodium1.361 g of Loxoprofen sodium dihydrate (equivalent to 1.2 gof Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 1.2% ofLoxoprofen sodium as a test sample.[Exampleiï¬ Externalformulationcontaining1%<ofLoxoprofensodium1.134 g of Loxoprofen sodium dihydrate (equivalent to 1 g ofLoxoprofen sodium) was dissolved in 4 ml of water.25CA 02264960 1999-02-26Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 1% ofLoxoprofen sodium as a test sample.[Example 4] External formulation containing 0.6% of Loxoprofensodium0.68 g of Loxoprofen sodium dihydrate (equivalent to 0.6 gof Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 0.6% ofLoxoprofen sodium as a test sample.[Example 5] External formulation containing 0.5% of Loxoprofensodium0.567 g of Loxoprofen sodium dihydrate (equivalent to 0.5 gof Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 0.5% ofLoxoprofen sodium as a test sample.[Example 6] External formulation containing 0.3% of Loxoprofensodium26CA 02264960 1999-02-260.34 g of Loxoprofen sodium dihydrate (equivalent to 0.3 gof Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 0.3% ofLoxoprofen sodium as a test agent.[Example 7] External formulation containing 0.25% of Loxoprofensodium0.284 g of Loxoprofen sodium dihydrate (equivalent to 0.25g of Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 0.25%of Loxoprofen sodium as a test agent.[Example 8] External formulation containing 0.15% of Loxoprofensodium0.17 g of Loxoprofen sodium dihydrate (equivalent to 0.15 gof Loxoprofen sodium) was dissolved in 4 ml of water.Then, the solution was treated in the same manner as describedin Example 1 to obtain an external formulation containing 0.15%of Loxoprofen sodium as a test agent.27CA 02264960 1999-02-26[Example9]Externalformulationcontaining1%<ofLoxoprofensodiumIn Example 2, similar process were carried out but using of1 g, instead of 2g, of crotamiton to obtain an external formulationcontaining 1% of Loxoprofen sodium as a test sample.[Example 10] Lotion containing 1% of Loxoprofen sodium1.134 g of Loxoprofen sodium dihydrate (equivalent to 1 g ofLoxoprofen sodium) was dissolved in 66.8 ml of water. 1 g ofcrotamiton and 0.25 g of peppermint oil were added to the mixtureof 0.2 g of sodium carboxymethylcellulose in 10 g of glycerol and20 g of propylene glycol and sufficiently mixed together. Thesolution of Loxoprofen.mentoined above was added to this mixuture,and 0.5 g of Tween 80 and 0.25 g of Span 20 as surfactants werethen added to the mixture whilst stirring to prepare a lotioncontaning 1 % of Loxoprofen sodium.[Example 11] External formulation containing 1% Loxoprofen11 .5 g of sodium polyacrylate and 27 g of glycerol were addedto the solution of 0.6 g of tartaric acid in 45.5 ml of water, andmixed together to prepare arnixture containing glycerol. Then, 2.5g of kaolin was added to the solution of 1 g of Loxoprofen in amixture of 2 g of crotamiton and 1 g of peppermint oil, then, the28CA 02264960 1999-02-26resulting mixture was sufficiently kneaded to prepare a mixturecontainingloxoprofen.ThenuxturecontainingLoxoprofmnwasaddedto the mixture containing glycerol whilst stirring, and 1 ml ofaqueous dispersion containing 0.05 g of aluminumthydroxide gel wasadded to the mixture and.mixed together. The weight of the mixtureobtaineclwas measured, andwdater was added thereto until the weightreached 100 g. The mixture was then sufficiently kneaded to preparean external formulation containing 1 % Loxoprofen.[Reference Example 1] External formulation containing a 1% oftrans-OH form11.5 % of sodium polyacrylate and 27 g of glycerol were addedto the solution of 0.6 g of tartaric acid in 45.5 ml of water, andmixed together to prepare arnixture containing glycerol. Then, 2.5g of kaolin.was added to the solution of lgyof trans-OH form, whichis an active metabolite, in a mixture of 2 g of crotamiton and 1<gofpeppermintoil,andtheresultingnuxturewasthensufficientlykneaded to prepare a mixture containing a trans-OH form. The mixturecontaining a trans-OH form was added to the mixture containingglycerol whilst stirring and 1nï¬.of aqueous dispersion containing0.05 g of aluminun1hydroxide gel was added to the mixture and.mixedtogether. The weight of the mixture obtained was measured, and29CA 02264960 1999-02-26water was added thereto until the total weight reached 100 g. Themixture was then sufficiently kneaded. The resulting externalformulation containing 1% of trans-OH form was spread over anonwoven fabric so as to occupy in an amount of 10 g/10x14 cm, anda polyethylene film was put on the formulation and the formulationwas cut into pieces of a certain desired size for use as a testsample.[Comparative Example 1]In Example 3, similar processes were carried out except thatcrotamiton was not used to obtain the external formulationcontaining 1% Loxoprofen sodium as a test sample.[Comparative Example 2]In Example 3, similar processes were carried out but using2 g of oleic acid instead of 2 g of crotamiton to obtain an externalformulation containing 1% Loxoprofen sodium asva test sample.[Comparative Example 3]In Example 3, similar processes were carried out but using2 g of isopropyl myristate instead of 2 g of crotamiton to obtainan external formulation containing 1% Loxoprofen sodium as a test30CA 02264960 2000-04-20sample[Test Example 1] Depositicniof crystals in the external formulationcontaining Loxoprofen sodium with the passage of timeImmediately afterlnanufacturing, with.regard.to the externalpatches obtained in Examples 1 and 9 and Comparative Examples 1to 3, the deposition of crystals of Loxoprofen sodium.was observedwith naked eye or under a microscope in the formulation. Then,samples were stored in an alminum pouch at room temperature, andthe deposition of crystals was observed with passage of time inthe same manner as described above.The results are shown in Table 1.Table 1 Deposition of crystals in the external formulationcontaining Loxoprofen sodium with the passage of timeNumber of days from the manufacturingFormulation date until crystals were depositedFormulation as described' ' f 2in Example 1 No deposition or yearsFormulation as described' ' f 2in Example 9 No deposition or yearsFormulation as described. 12 din Comparative Example 1 aysFormulation as describedin Comparative Example 24 monthsFormulation as described, , 4 daysin Comparative Example 331CA 02264960 2000-04-20As shown clearly in Table 1, no Loxoprofen was deposited.overa long period of time in the formulations as described in Examples1 and 9 which contain crotamiton as a solvent. That is, the additionof crotamiton significantly improved.the stability of the externalformulations containing Loxoprofen sodium.[Test Example 2] Permeability tests for in vitro skin of externalformulations containing Loxoprofen sodiumThe external patches obtained as described in Example 3,Comparative Example 1, and Reference Example 1 were subjected topermeability tests for in Vi tro using rat skin. The concentrationsof Loxoprofen, per se, and of the trans-OH form, which is an activemetabolite, were measured to examine their skin permeability afterapplication.Each of externalpatches of 1 cm in diameter was used for tests .Sodium pentobarbital was intraperitoneally administered ina content of lmg/kg to Wistar Imamichi male rats (7 weeks of age),which were then put under anesthesia. After that, a hair clipperand a shaver were used to shave hair on the abdomen. Then, the skinwas picked out therefrom in the form of a disk of 2 .2 cm in diameter.The fat layer under the corium tissue of the skin picked out was32CA 02264960 1999-02-26removed, and the resulting skin was fixed to a vertical diffusioncell for permeability tests, which had been maintained beforehandat 37°C. The formulation was applied to the stratum corneumepidermidis on the diffusion cell, and 4.5 ml of Tyrode's solutionwas added to the dermal layer side as a receiver solution. Duringa 24-hour patch test, 0.5 ml of receiver solution was occasionallysampled as appropriate and was subjected to HPLC to measure theconcentration of the drug. When the receiver liquid was sampled,0.5 ml of Tyrode's solution without drug, being kept warm at 37°C,was added to maintain the Volume of the receiver liquid constant.The cumulative amount of the drug after skin permeation increasedlinearly with the passage of time.The HPLC measurement method is shown below.An equal amount of ethanol solution [10 mg/ml of ethyl p-hydroxybenzoate (produced by Wako Pure Chemical Industry Co.,Ltd.)] as an internal standard was added to the samples taken outand admixed together. The mixture was centrifuged at 12,000 rpmfor 5 minutes, and the supernatants were used as samples for HPLC.HPLC measuring conditionsColumn: CAPCELLPACK C18 (4.6 x 150 mm; produced by Shiseido Co.,Ltd.)33CA 02264960 2000-04-20Mobile phase: 1% phosphoric acid/acetonitrile=5/2Column temperature: 40°CFlow rate: 1 ml/min.Detected wavelength: 222 nmRetention time: Loxoprofen: 12.7 minutestrans-OH form: 10.7 minutescisâOH form: 11.9 minutesethyl pâbenzoate: 7.6 minutesThe results are shown in Table 2.Table2 Permeabilitytestsforinvitroskinofexternalformulationscontaining Loxoprofen sodiumSkin permeation flux (nmol/cmz/hr)FormulationLoxoprofen TransâOH formFormulation as described 2 . SO 1. 25in Example 3Formulation as described 1.25 O ' 35in Comparative Example 1Formulation as described. 0.50in Reference Example 134CA 02264960 1999-02-26The results of the tests using formulations as described inExampleZ3andComparativeExample1.clearlyindicatethatLoxoprofensodium is surprisingly converted into a trans-OH form, which isit's active metabolite, in the skin without passing through theliver or kidney. In addition, when the formulations as describedin Example 3 and Comparative Example 1 are compared together, theaddition of crotamiton served to double the permeation rate ofLoxoprofen and quadruple the increasing rate of the trans-OH formin the receiver liquid (this can be considered to correspond tothe trans-OH form which would exist under the dermal layer). Asa result, a very large amount of trans-OH form was present in thereceiver solution in a certain time after the application of theformulation.In addition, the results of the formulation as described inReference Example 1 indicate that the trans-OH form, which is anactive metabolite, showed low permeability through the skin andthat the increasing rate of the trans-OH form in the receiversolution was small even when the trans-OH form. per se wasadministered. When these results are compared.with the results ofthe formulation.as described.in Example 3, it is found.unexpectedlythat when Loxoprofen sodium, which iseaprodrug, was administered,the increasing rate of the trans-OH form in the receiver liquid35CA 02264960 1999-02-26was higher, resulting in a larger amount of trans-OH form in thereceiver liquid.[Test Example 3] Concentration in tissues of metabolites after theapplication of external formulations containing Loxoprofen sodiumto skin. 'Patches produced according to the method as described inExample 3, labeled with âC and containing 1% of Loxoprofen sodium,were applied to the skin on the back of rats for 4, 8, and 24 hours,concentrations of active metabolites in the dermal tissue of theskin and in blood plasma were measured.Body hair on the back of Wistar Imamichi male rats (7 to 8weeks of age; three rats in each group) was removed using a hairclipper and a shaver, and formulation pieces in a size of 2 x 1.75cm were applied on the skins of the rats. The blood plasma (0.5to 2 ml) was sampled at each different times from the rats to whichthe formulation was applied and the rats were then sacrificed. Bystripping sufficiently by use of a cellophane adhesive tape, thestratum corneunxwas removed from the skin in the middle of the siteto which the formulation was applied. A.punch (E 1.0 cm) was usedto punch the corium portion out to remove it. The removed portionwas hashed after fat and capillaries were removed from the corium36CA 02264960 1999-02-26portion. Then, a quintuple amount of methanol was added to thehashed skin slices to homogenize it, and the resulting mixture wascentrifuged at 1,800 x g and 4°C for 10 minutes to obtain thesupernatant as an extract. The blood plasma mentioned above wassimilarly treated on to obtain an extract. After each extract wasdried and solidified under reduced pressure at room temperature,it was redissolved in a small amount of methanol and was subjectedto thin layer chromatography (TLC) to measure the concentrationof active metabolites.MeasurementsbasedontheTlcnwthodwereexecutedasfollows.The sample in methanol mentioned above was applied in linesto a TLC plate (silica gel 6OF254; Art No. 5714, manufactured byMERCK Co.) together with the authentic sample of Loxoprofen perse and its metabolite, and a solution of benzenezacetonezaceticacid(80:l5:5)wasusedasaadevelopingsolventtodevelopthesamplethree times so that the length of the developing solvent reached15 cm. After development, the TLC plate was dried and covered witha protective film (4um; manufactured by DIAFOIL Co.), and was thenadhered to an imaging plate (TYPEâBA; manufactured by Fuji FilmCo., Ltd.) and exposed in a lead sealed box for 24 hours. Afterexposure, a bioâimage analyzer (FUJIX BA100; manufactured by FUJIFilm Co., Ltd.) was used to read a radioâactive image on imaging37CA 02264960 1999-02-26plate to create an autoradiogram. The developed position of theauthentic sample of the metabolite was confirmed using a 254ânmultraviolet lamp. Then, the autoradiogram was fractionated intoa background section and a radio-active band region of Loxoprofen(an unchanged form) or transâOH form (an active metabolite)Itocalculate from each emission intensity the ratios of Loxoprofen(an unchanged form) and trans-OH form (an active metabolite).The concentrations of Loxoprofen (an unchanged form) andtrans-OH form (an active metabolite) were calculated in thefollowing manner.The concentrations were determined using the totalconcentration calculated from the radio-active concentration ofthe sample prior to the TLC operation as well as the ratioscalculated above.The results are shown in Table 3.38CA 02264960 1999-02-26Table 3 Concentration of Loxoprofen metabolites in the tissues<ug/g or ug/ml)Tissue Time Loxoprofen Trans-OH form4 hours 61.04 4.17Corium laYer 8 hours 60.16 4 oo(uq/g)24 hours 60.48 ' 3.734 hours 0.20 0.11Blood plasma 8 hours 0.28 0.17(pg/ml)24 hours 0.13 0.12As shown clearly in Table 3, the concentration of trans-OHform, which is an active metabolite, in the dermal layer was 40times higher than that in the blood plasma, and the concentrationof Loxoprofen, which is an unchanged form, in the dermal layer was300timeshigherthanthatiJ1thebloodplasma. ThisindicatesthatLoxoprofen sodium transferred directly to the topical site.Furthermore, since its amount remained constant duringadministration, this indicates that this formulation providessufficient efficacy when applied once a day.[Test Example 4] Suppression of carrageenin crural edemaThe external patches of Loxoprofen sodium as described inExamples 2, 4, 6, and 8 were investigated for carrageenin cruraledema suppression effect.39CA 02264960 1999-02-26SD male rats (5 weeks of age) were used for the tests, with8ratsconstitutingeachgroup. Thehaircnitheleftposteriorfeetof the rats was shaven using an electric hair clipper, and 0.1 mlof 0.5% saline solution of carrageenin was injected under the footsole skin of the left posterior foot to induce inflammation.Immediately after inflammation was induced, formulation in a sizeof 2 X 1.75 cm were applied to the feet, and the volume of the footsole was measured at 1, 2, 3, 4, and 5 hours after the inductionto observe the inflammation suppression effect of the presentexternal formulation using as an edema rate the increasing ratein the volume of the foot sole after the induction of inflammationrelative to the same volume prior to the injection of theinflammation inducing agent. The suppression effect reached itsmaximum value at 4 hours after the induction.For comparison, a "control group" was provided in whichinflammation was induced as described above and in which rats werethen left untreated.Furthermore, a "base group" was provided in which rats weretreated using a formulation of the same composition as describedin Example 1 except for the absence of Loxoprofen sodium.The results are shown in Table 4.40CA 02264960 1999-02-26Table 4 Rat carrageenin edema suppression effect(4 hours after induction)Formulation Edema rate (%) Suppression(averageistandard error) rate(%)Control group 65.2 i 4.7Base group 58.6 i 4.7 ' 10.2des::§§:d@Ei§:a::le2 31â2 i 3â1** 52'1des::f::d:E:§:a;:le4 33'3 i 3'1** 48'9des§§f£â§§âiEf§§a£§1e 5 36-3 3-â 3-0* 43-4des§ff£§â§§iZl§§a§§1e8 333 3 4~4* 41-3Significant difference from the base group*:p < 0.01, **: p < 0.001As shown.clearly'in'Table 4, the formulation.containing 0.15%or more of Loxoprofen sodiunlwas observed to exhibit a significantsuppression effect against the control and base groups dependingon the concentration. Thus, it is evident that this formulationis effective on acute inflammation.[Test Example 5] Anti-inflammatory effect on adjuvant arthritisThe patches containing Loxoprofen sodium as described inExamples 1, 3, 5, and 7 were investigated for anti-inflammatoryeffect on adjuvant arthritis.41CA 02264960 1999-02-26Lewis male rats (8\~eeks of age) were used for the tests, with10 rats constituting one group. Mygghag;g;igm,hu;y;1gnm that hadbeen killed by heating were refined, and the refined cells werethensuspendedinliquidparaffinuntilthevolumecï¬fthesuspensionreached 6 mg/ml. The suspension was then sterilized at 120°C andusadasanadjuvant. Thevolumeofbothposteriorfeetwasmeasured,and 0.1 ml of the killed cell suspension, which had been heatedup to 50°to 60°C, was injected.into the tail.base skin. An adjuvantwasadministeredtotheratsforwhichinflammationhadbeeninduced,and 19 days later, formulation pieces 2 x 1.75 cm in size into whichthe formulation had been cut were each applied to the peripheryofthesoleoftherightposteriorfeet. Theformulationwasallowedto remain application for 9 consecutive days. The increase in thevolume of the soles of both posterior feet on the day whenapplicationwasstartedwasdefinedasaal00%edemarate,andchangesin this volume were observed every day.The "control group" and "base group" were the same asdescribed in [Test Example 4].The results are shown in Table 5.42CA 02264960 1999-02-26Table 5 Antiâinflammatory effect on the adjuvant arthritisEdema rate(%)(average i standard error)FormulationThe number enclosed in parentheses indicatesthe edema suppression rate(%)21 days 26 days 31 days|+.12.Control group 93.1 .77 86.7 i 5.57 79.6 i 3.9881.4 i 4.70 73.1 i 3.89 65.4 i 3.89Base group 5 7Formulation asdescribed inExample 152.3 i 2.38* 48.0 i 3.20*74.4 i0 (39.6) (39.8)4.00)Formulation asdescribed in69.1 i 4.77 51.6 i 2.38*Example 3 5.8) (40.5) (41.7)Formulation asdescribed in 76.6 :r 3.99 59.0 1 2.38* 50.2 : 2.39*Example 5 (17 7) (32.2) (36.9)Fggggï¬fgggnigs 75.2 : 5.43 61.3 : 3.10 59.3 : 3.85Example 7 (19.2) (29.3) (25 6)Significant difference from the base group *:As shown clearly in Table 5, the formulation containing 0.5%or more of Loxoprofen sodium was confirmed to provide a significantsuppression effect against the control and base groups dependingon the concentration. Thus, this formulation is clearly effectiveon chronic inflammation.43CA 02264960 1999-02-26Industrial ApplicabilityBy addition of crotamiton as a solvent to an externalformulation containing Loxoprofen or its pharmaceuticallyacceptable salt, Loxoprofen is prevented from being deposited incrystal form, and it is thus possible to provide a formulation whoseactive ingredients are distributed appropriately. Thisformulation enables a substantial increase in the rate and amountof transcutaneous absorption of Loxoprofen, and also enables thesustainedsupplyoflpxoprofen,ix)alhmvasufficientconcentrationof Loxoprofen to be continuously accumulated in the skin at theapplied site. Then, Loxoprofen is transformed into the trans-OHform in the skin, thus enabling a sufficient amount of transâOHform to be provided at the applied site. As a result, theapplication of this formulation can provide an excellent topicalanalgesic effects. The anti-inflammatory analgesic externalformulation of this invention shows less irritation on the skinand is effective in the prevention or treatment of, for example,osteoarthritis, rheumatoid arthritis, lumbago, scapulohumeralperiarthritis,tendovaginitis,inflammationoftendonperipheries,humeral epicondylitis (tennis elbow), muscle pain, or swelling orpain after trauma.44
Claims (38)
1. A method for producing a traps-OH form comprising converting Loxoprofen or its pharmaceutically acceptable salt into traps-OH form thereof with a ketone-reducing enzyme existing in the skin.
2. An anti-inflammatory analgesic external formulation containing Loxoprofen or its pharmaceutically acceptable salt and crotamiton.
3. The anti-inflammatory analgesic external formulation according to Claim 2, wherein application of the external formulation causes Loxoprofen or its pharmaceutically acceptable salt to be metabolized into a traps-OH form thereof in the skin and wherein the concentration of traps-OH form is higher in a dermal layer of the skin at an applied site than in blood plasma.
4. The anti-inflammatory analgesic external formulation according to Claim 2 or 3, wherein the content of crotamiton is 0.5 to 5% by weight of the total weight of the formulation.
5. An anti-inflammatory analgesic external formulation according to Claim 2 or 3, wherein the content of crotamiton is 1 to 2% by weight of the total weight of the formulation.
6. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 5, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.1 to 5% by weight of the total weight of the formulation.
7. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 5, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.15 to 2% by weight of the total weight of the formulation.
8. The anti-inflammatory analgesic external formulation according to any of claims 2 to 5, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.5 to 2% by weight of the total weight of the formulation.
9. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 8, wherein the content of a solvent and/or a skin permeation accelerator is 0.5 to 80% by weight of the total weight of the formulation.
10. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 9, wherein the content of a water-soluble polymer is 3 to 30% by weight of the total weight of the formulation.
11. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 9, wherein the content of a water-soluble polymer is 5 to 20% by weight of the total weight of the formulation.
12. An anti-inflammatory analgesic external formulation according to any of Claims 2 to 11, wherein the content of an oil-soluble polymer is 5 to 95% by weight of the total weight of the formulation.
13. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 11, wherein the content of an oil-soluble polymer is 10 to 80% by weight of the total weight of the formulation.
14. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 13, wherein the content of a moisturizer is 5 to 60% by weight of the total weight of the formulation.
15. The anti-inflammatory analgesic external formulation according to any of Claims 2 to 13, wherein the content of a moisturizer is 10 to 45% by weight of the total weight of the formulation.
16. The formulation according to any of Claims 2 to 15, wherein the anti-inflammatory analgesic external formulation is a patch.
17. The formulation according to any of Claims 2 to 15, wherein the anti-inflammatory analgesic external formulation is an ointment.
18. The formulation according to any of Claims 2 to 15, wherein the anti-inflammatory analgesic external formulation is a cream.
19. The formulation according to any of Claims 2 to 15, wherein the anti-inflammatory analgesic external formulation is a lotion.
20. The formulation according to any of Claims 2 to 15, wherein the anti-inflammatory analgesic external formulation is an aerosol.
21. An anti-inflammatory analgesic external formulation containing Loxoprofen or its pharmaceutically acceptable salt and crotamiton for use in the production of a trans-OH form of Loxoprofen or its pharmaceutically acceptable salt, comprising converting Loxoprofen or its pharmaceutically acceptable salt into the trans-OH form with a ketone-reducing enzyme existing in the skin.
22. The anti-inflammatory analgesic external formulation according to Claim 21, wherein the content of crotamiton is 0.5 to 5% by weight of the total weight of the formulation.
23. The anti-inflammatory analgesic external formulation according to Claim 21, wherein the content of crotamiton is 1 to 2% by weight of the total weight of the formulation.
24. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 23, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.1 to 5%
by weight of the total weight of the formulation.
by weight of the total weight of the formulation.
25. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 23, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.15 to 2%
by weight of the total weight of the formulation.
by weight of the total weight of the formulation.
26. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 23, wherein the content of Loxoprofen or its pharmaceutically acceptable salt is 0.5 to 2%
by weight of the total weight of the formulation.
by weight of the total weight of the formulation.
27. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 26, wherein the content of a solvent and/or a skin permeation accelerator is 0.5 to 80% by weight of the total weight of the formulation.
28. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 27, wherein the content of a water-soluble polymer is 3 to 30% by weight of the total weight of the formulation.
29. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 27, wherein the content of a water-soluble polymer is 5 to 20% by weight of the total weight of the formulation.
30. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 29, wherein the content of an oil-soluble polymer is 5 to 95% by weight of the total weight of the formulation.
31. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 29, wherein the content of an oil-soluble polymer is 10 to 80% by weight of the total weight of the formulation.
32. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 31, wherein the content of a moisturizer is 5 to 60% by weight of the total weight of the formulation.
33. The anti-inflammatory analgesic external formulation according to any of Claims 21 to 31, wherein the content of a moisturizer is 10 to 45% by weight of the total weight of the formulation.
34. The formulation according to any of Claims 21 to 33, wherein the anti-inflammatory analgesic external formulation is a patch.
35. The formulation according to any of Claims 21 to 33, wherein the anti-inflammatory analgesic external formulation is an ointment.
36. The formulation according to any of Claims 21 to 33, wherein the anti-inflammatory analgesic external formulation is a cream.
37. The formulation according to any of Claims 21 to 33, wherein the anti-inflammatory analgesic external formulation is a lotion.
38. A formulation according to any of Claims 21 to 33, wherein the anti-inflammatory analgesic external formulation is an aerosol.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPHEI8-223524 | 1996-08-26 | ||
| JP22352496 | 1996-08-26 | ||
| PCT/JP1997/002936 WO1998008966A1 (en) | 1996-08-26 | 1997-08-25 | Loxoprofen-containing preparation for external use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2264960A1 CA2264960A1 (en) | 1998-03-05 |
| CA2264960C true CA2264960C (en) | 2003-04-22 |
Family
ID=16799501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002264960A Expired - Lifetime CA2264960C (en) | 1996-08-26 | 1997-08-25 | External formulation containing loxoprofen |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US6248350B1 (en) |
| EP (1) | EP0947584B1 (en) |
| JP (3) | JPH10120560A (en) |
| KR (2) | KR100456668B1 (en) |
| CN (2) | CN1231700A (en) |
| AT (1) | ATE510531T1 (en) |
| AU (1) | AU728797B2 (en) |
| BR (1) | BR9711368A (en) |
| CA (1) | CA2264960C (en) |
| DK (1) | DK0947584T3 (en) |
| ES (1) | ES2365203T3 (en) |
| WO (1) | WO1998008966A1 (en) |
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| US20090297602A1 (en) * | 1998-11-02 | 2009-12-03 | Devane John G | Modified Release Loxoprofen Compositions |
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| US7309688B2 (en) * | 2000-10-27 | 2007-12-18 | Johnson & Johnson Consumer Companies | Topical anti-cancer compositions and methods of use thereof |
| US8431550B2 (en) | 2000-10-27 | 2013-04-30 | Johnson & Johnson Consumer Companies, Inc. | Topical anti-cancer compositions and methods of use thereof |
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| BR0314084A (en) * | 2002-09-07 | 2005-07-05 | Johnson & Johnson Consumer Fr | Compositions comprising soy products and organic salts of certain metals |
| EP1559426B1 (en) * | 2002-11-05 | 2011-02-09 | Lead Chemical Co. Ltd. | Percutaneous absorption preparations containing 3-methyl-1-phenyl-2-pyrazolin-5-one |
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| JP2011037903A (en) * | 2010-11-26 | 2011-02-24 | Daiichi Sankyo Co Ltd | Antiinflammatory/analgesic composition for external use |
| KR20140035879A (en) * | 2011-01-24 | 2014-03-24 | 니프로 패치 가부시키가이샤 | Hydrous adhesive patch |
| JP5280472B2 (en) * | 2011-03-02 | 2013-09-04 | 第一三共株式会社 | Anti-inflammatory analgesic composition for external use |
| JP6144944B2 (en) * | 2012-03-29 | 2017-06-07 | 興和株式会社 | Pharmaceutical composition containing loxoprofen |
| KR20140100422A (en) * | 2013-02-05 | 2014-08-14 | 닛토덴코 가부시키가이샤 | Vaccine composition |
| JP6060742B2 (en) * | 2013-03-08 | 2017-01-18 | ライオン株式会社 | Liquid composition for external use |
| EP2982369A4 (en) * | 2013-04-01 | 2016-11-02 | Daiichi Sankyo Co Ltd | Preparation for treating equine inflammation |
| JP6189668B2 (en) * | 2013-07-31 | 2017-08-30 | 興和株式会社 | Loxoprofen-containing external coating |
| JP2015083563A (en) * | 2013-09-18 | 2015-04-30 | 第一三共ヘルスケア株式会社 | Loxoprofen-containing external liquid preparation for skin |
| EP2926810A1 (en) | 2014-03-31 | 2015-10-07 | Sanovel Ilac Sanayi ve Ticaret A.S. | Oral liquid pharmaceutical formulations of loxoprofen |
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| CN109776300B (en) * | 2019-02-28 | 2020-08-07 | 浙江大学 | Synthetic method of loxoprofen sodium |
| CN111635309B (en) * | 2019-03-01 | 2024-03-12 | 华创合成制药股份有限公司 | Novel antipyretic analgesic medicine and preparation method and application thereof |
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| CN113121331B (en) * | 2019-12-31 | 2024-01-05 | 华创合成制药股份有限公司 | Phenoxy aromatic acid compounds with cyclopropyl and pharmaceutically acceptable salts thereof, and preparation methods and applications thereof |
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| CN113069437A (en) * | 2020-12-29 | 2021-07-06 | 北京湃驰泰克医药科技有限公司 | External gel emplastrum containing loxoprofen and medicinal salt thereof and preparation method thereof |
| CN115444837B (en) * | 2022-10-13 | 2023-08-22 | 湖南九典制药股份有限公司 | Loxoprofen transdermal drug delivery system and preparation method thereof |
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1997
- 1997-08-22 JP JP9226020A patent/JPH10120560A/en active Pending
- 1997-08-25 KR KR10-1999-7001529A patent/KR100456668B1/en not_active IP Right Cessation
- 1997-08-25 BR BR9711368A patent/BR9711368A/en not_active Application Discontinuation
- 1997-08-25 WO PCT/JP1997/002936 patent/WO1998008966A1/en active IP Right Grant
- 1997-08-25 EP EP97935867A patent/EP0947584B1/en not_active Expired - Lifetime
- 1997-08-25 ES ES97935867T patent/ES2365203T3/en not_active Expired - Lifetime
- 1997-08-25 CN CN97198272A patent/CN1231700A/en active Pending
- 1997-08-25 US US09/242,555 patent/US6248350B1/en not_active Expired - Lifetime
- 1997-08-25 DK DK97935867.8T patent/DK0947584T3/en active
- 1997-08-25 CN CN200910009743A patent/CN101658486A/en active Pending
- 1997-08-25 AT AT97935867T patent/ATE510531T1/en active
- 1997-08-25 KR KR10-2003-7008523A patent/KR100403486B1/en not_active IP Right Cessation
- 1997-08-25 AU AU38686/97A patent/AU728797B2/en not_active Expired
- 1997-08-25 CA CA002264960A patent/CA2264960C/en not_active Expired - Lifetime
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2007
- 2007-05-29 JP JP2007141490A patent/JP2007291118A/en active Pending
- 2007-12-11 JP JP2007320033A patent/JP5137548B2/en not_active Expired - Lifetime
Also Published As
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|---|---|
| JP5137548B2 (en) | 2013-02-06 |
| KR100403486B1 (en) | 2003-11-01 |
| ATE510531T1 (en) | 2011-06-15 |
| CN101658486A (en) | 2010-03-03 |
| DK0947584T3 (en) | 2011-07-18 |
| EP0947584B1 (en) | 2011-05-25 |
| JP2007291118A (en) | 2007-11-08 |
| WO1998008966A1 (en) | 1998-03-05 |
| AU728797B2 (en) | 2001-01-18 |
| US6248350B1 (en) | 2001-06-19 |
| KR100456668B1 (en) | 2004-11-10 |
| EP0947584A1 (en) | 1999-10-06 |
| CN1231700A (en) | 1999-10-13 |
| WO1998008966A8 (en) | 1999-08-19 |
| BR9711368A (en) | 1999-08-17 |
| CA2264960A1 (en) | 1998-03-05 |
| EP0947584A4 (en) | 2002-10-23 |
| JP2008074873A (en) | 2008-04-03 |
| KR20000030025A (en) | 2000-05-25 |
| JPH10120560A (en) | 1998-05-12 |
| AU3868697A (en) | 1998-03-19 |
| ES2365203T3 (en) | 2011-09-26 |
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